Fragmented early-life experiences, aberrant circuit maturation, emotional vulnerabilities

这项跨学科的中心更新建议解决了影响认知的早期环境信号 以及情绪结果和这些信号调节大脑发育的机制 潜藏在情绪和认知中的回路。我们已经深刻地确定了母体信号的模式 影响认知和情绪发展：具体地说，不可预测和支离破碎的 从胎儿期开始的母亲情绪和行为(FRAG)增加了内化症状的风险 这预示着从婴儿期到青春期的快感缺乏和认知障碍。重要的是， FRAG是对先前确定的影响(例如，母亲抑郁、焦虑、敏感)的补充。 在这份修订后的续签申请中，我们受益于审查员的建议，并利用了一群儿童 在最初的获奖期内发展起来的，我们在出生前和出生后都有前所未有的接触 历史，以检验FRAG是一种影响心理健康结果的新形式的逆境的假设 通过大脑回路的异常成熟。扩展我们现有的认知和情绪评估 考虑到暴露和评估时的性别和年龄是重要的变量，我们将强调快感缺乏， 一种新的跨物种识别的FRAG结果作为重要的跨诊断指标具有新的意义 精神疾病中的次元实体。我们将检查3-6岁儿童快感缺乏的早期表现。 使用空间RDoC方法的儿童，确定增加其风险的新的母体信号 表达，识别机制和生物标记物，分别专注于正常大脑的破坏 电路发育和表观遗传特征。因此，我们将利用我们的尖端神经成像技术， 个体内甲基组学和新的评估工具来检验以下假设：(1)早期生命 暴露在支离破碎和不可预测的母体信号中会增加3-6岁儿童快感缺乏症的风险 孩子们。(2)暴露在支离破碎和不可预测的早期家庭环境中会增加患上 3~6岁儿童快感缺失。(3)早年接触支离破碎和不可预测的母亲 而环境信号通过破坏大脑中的神经细胞，增加了儿童早期快感缺乏的风险 愉悦/奖赏大脑回路和来自同一样本的两对样本中的甲基组变化(签名) 婴儿将提供这种风险的预测性生物标志物。

This trans-disciplinary Center renewal proposal addresses early environmental signals that influence cognitive and emotional outcomes and the mechanisms by which these signals modulate the development of brain circuits underlying emotion and cognition. We have identified that patterns of maternal signals profoundly influence cognitive and emotional development: Specifically, unpredictable and fragmented patterns of maternal mood and behavior (FRAG) beginning in the fetal period increase the risk for internalizing symptoms that presage anhedonia and cognitive impairments in infancy through adolescence. Importantly, the effects of FRAG are additional to those of previously identified influences (e.g. maternal depression, anxiety, sensitivity). In this revised renewal application we benefit from Reviewer suggestions and capitalize on a cohort of children developed during the original award period for whom we have an unprecedented pre and postnatal exposure history, to test the hypothesis that FRAG is a novel form of adversity that influences mental health outcomes via aberrant maturation of brain circuits. Extending our existing cognitive and emotional assessments and considering sex and ages at exposure and assessment as important variables, we will emphasize anhedonia, a novel FRAG outcome identified across species with emerging significance as an important transdiagnostic dimensional entity in mental illness. We will examine the early manifestation of anhedonia in 3-6 year old children using a dimensional RDoC approach, determine novel maternal signals that increase risk for its expression, and identify mechanisms and biomarkers focusing, respectively, on disruption of normal brain circuit development and epigenetic signatures. Thus, we shall capitalize on our cutting edge neuroimaging, intra-individual methylomics and novel assessment tools to test the following hypotheses: (1) that early life exposure to fragmented and unpredictable maternal signals increases risk for anhedonia in 3 to 6-year-old children. (2) that exposure to a fragmented and unpredictable early life home environment increases the risk of anhedonia in 3 to 6-year-old children. (3) that early life exposure to fragmented and unpredictable maternal and environmental signals increases risk for anhedonia in early childhood through the disruption of pleasure/reward brain circuits and that methylome changes (signatures) in two paired samples from the same infant will provide predictive biomarkers of this risk.